U.S. patent number 7,931,932 [Application Number 12/070,275] was granted by the patent office on 2011-04-26 for processes for producing polymer coatings through surface polymerization.
This patent grant is currently assigned to Boston Scientific Scimed, Inc.. Invention is credited to Peter L. Dayton, Robert A. Herrmann, Wendy Naimark, Frederick H. Strickler.
United States Patent |
7,931,932 |
Herrmann , et al. |
April 26, 2011 |
Processes for producing polymer coatings through surface
polymerization
Abstract
A medical device with a therapeutic agent-releasing polymer
coating. The medical device is provided by a method that comprises:
(a) attaching at least one reactive species to a medical device
surface, which reactive species leads to chain growth
polymerization in the presence of monomer; (b) contacting the
reactive species with at least one monomer species, thereby forming
a polymer coating on the surface of the medical device; and (c)
providing at least one therapeutic agent within the polymer
coating. The therapeutic agent may be incorporated during formation
of the polymer coating or after formation of the polymer coating.
The at least one reactive species can comprise, for example, a free
radical species, a carbanion species, a carbocation species, a
Ziegler-Natta polymerization complex, a metallocene complex, and/or
an atom transfer radical polymerization initiator. Alternatively,
the medical device is provided by a process comprising: (a)
immobilizing least one polymerization catalyst at a medical device
surface, which polymerization catalyst leads to polymerization in
the presence of monomer; (b) contacting the medical device surface
with at least one monomer species, thereby forming a polymer
coating at the surface of the medical device; and (c) providing at
least one therapeutic agent within the polymer coating.
Inventors: |
Herrmann; Robert A. (Boston,
MA), Strickler; Frederick H. (Natick, MA), Naimark;
Wendy (Boston, MA), Dayton; Peter L. (Brookline,
MA) |
Assignee: |
Boston Scientific Scimed, Inc.
(Maple Grove, MN)
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Family
ID: |
28789846 |
Appl.
No.: |
12/070,275 |
Filed: |
February 14, 2008 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20080145516 A1 |
Jun 19, 2008 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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10116647 |
Apr 4, 2002 |
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Current U.S.
Class: |
427/2.1;
623/1.11; 424/425; 525/269; 427/2.25; 623/1.42; 427/372.2;
427/2.24 |
Current CPC
Class: |
A61L
31/10 (20130101); A61L 31/16 (20130101); A61L
2300/606 (20130101) |
Current International
Class: |
B05D
3/06 (20060101); C08F 2/46 (20060101); A61F
2/06 (20060101); C08F 295/00 (20060101) |
Field of
Search: |
;427/2.1,2.24,2.25,487
;623/1.11,1.42 ;424/425 ;525/269 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 00/59963 |
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Oct 2000 |
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WO |
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WO 01/17575 |
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Mar 2001 |
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WO |
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WO 02/058753 |
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Aug 2002 |
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WO |
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WO 02/070022 |
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Sep 2002 |
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WO |
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Other References
Hester et al. ATRP of Amphiphilic graft copolymers bond on pVDF and
their use as membrane additives. Macromolecules. 2002. vol. 35 pp.
7652-7661. cited by examiner.
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Primary Examiner: Meeks; Timothy H
Assistant Examiner: Sellman; Cachet I
Attorney, Agent or Firm: Mayer & William PC Bonham;
David B. Park; Keum J.
Parent Case Text
STATEMENT OF RELATED APPLICATION
This is a continuation of U.S. patent application Ser. No.
10/116,647, filed Apr. 4, 2002, now abandoned, entitled "Processes
for Producing Polymer Coatings Through Surface Polymerization,"
which is incorporated herein by reference in its entirety.
Claims
The invention claimed is:
1. A method of providing a medical device with a therapeutic
agent-releasing polymer coating comprising: (a) covalently
attaching an atom transfer radical polymerization initiator
molecule to a medical device surface; (b) contacting said initiator
molecule with at least one monomer species in the presence of an
atom transfer radical polymerization catalyst, thereby forming a
polymer coating on the surface of the medical device; (c) providing
at least one therapeutic agent within said polymer coating; and (d)
cross-linking said polymer coating.
2. The method of claim 1, wherein at least one therapeutic agent is
incorporated during formation of the polymer coating.
3. The method of claim 1, wherein at least one therapeutic agent is
incorporated after formation of the polymer coating.
4. The method of claim 1, wherein the medical device is an
implantable or insertable medical device.
5. The method of claim 4, wherein the medical device is a
stent.
6. The method of claim 1, wherein said at least one monomer species
comprises an unsaturated monomer.
7. The method of claim 1, wherein said polymer is selected from the
group consisting of polyalkylenes and derivatives, vinyl polymers
and derivatives, acrylic acid polymers and derivatives, and
copolymers thereof.
8. The method of claim 1, wherein said polymer is selected from the
group consisting of ethylene vinyl acetate and styrene-isobutylene
copolymers.
9. A method of providing a medical device with a therapeutic
agent-releasing coating comprising: (a) immobilizing at least one
polymerization catalyst at a medical device surface, said
polymerization catalyst leading to polymerization in the presence
of monomer; (b) contacting the medical device surface with at least
one monomer species, thereby forming a polymer coating at the
medical device surface; (c) providing at least one therapeutic
agent within said polymer coating; and (d) cross-linking said
polymer coating.
10. The method of claim 9, wherein the at least one polymerization
catalyst is immobilized by covalently bonding it to said
surface.
11. The method of claim 9, wherein the medical device surface is at
least partially covered by a metal catalyst.
12. The method of claim 9, wherein at least one therapeutic agent
is provided within the polymer coating during formation of the
polymer coating.
13. The method of claim 9, wherein at least one therapeutic agent
is provided within the polymer coating after formation of the
polymer coating.
14. The method of claim 9, wherein the medical device is an
implantable or insertable medical device.
15. The method of claim 14, wherein the medical device is a
stent.
16. The method of claim 9, wherein said polymer is selected from
the group consisting of ethylene vinyl acetate copolymers,
poly(.epsilon.-caprolactone), styrene-isobutylene copolymers and
silicone.
17. A method of providing a medical device with a therapeutic
agent-releasing coating comprising: (a) immobilizing at least one
polymerization catalyst at a medical device surface by physically
embedding said polymerization catalyst in said surface, said
polymerization catalyst leading to polymerization in the presence
of monomer; (b) contacting the medical device surface with at least
one monomer species, thereby forming a polymer coating at the
medical device surface; and (c) providing at least one therapeutic
agent within said polymer coating.
18. A method of providing a medical device with a therapeutic
agent-releasing coating comprising: (a) immobilizing at least one
polymerization catalyst at a medical device surface, said
polymerization catalyst leading to polymerization in the presence
of monomer; (b) contacting the medical device surface with at least
one monomer species, thereby forming a polymer coating at the
medical device surface, wherein the at least one monomer species
comprises a dendrimer; and (c) providing at least one therapeutic
agent within said polymer coating.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to medical devices with polymeric
coatings and more particularly to medical devices having polymer
coatings that release therapeutic agent.
2. Brief Description of the Background Art
Local delivery of therapeutic agents is an important adjunct to
mechanical treatment of diseases. For example, local delivery of
restenosis-inhibiting therapeutic agents has been proposed in
connection with the insertion of a coronary stent after
percutaneous transluminal coronary angioplasty, as the presence of
the stent can exacerbate neointimal hyperplasia, which is believed
to be a significant causative factor in the restenosis of the
vessel.
One common method of local therapeutic agent delivery is to allow
the therapeutic agent to diffuse from a polymer matrix. In this
connection, controlling release is an important aspect in providing
effective therapy. Furthermore, controlling the manufacture of the
polymer matrix is an important factor in determining the ultimate
release rate.
SUMMARY OF THE INVENTION
The present invention provides a method of producing a polymer on a
medical device in which polymer chains are grown at the surface of
the medical device to provide a polymer coating.
According to one aspect of the presenting invention, a medical
device with a therapeutic agent-releasing polymer coating is
provided by a method that comprises: (a) attaching at least one
reactive species to a medical device surface, which reactive
species leads to chain growth polymerization in the presence of
monomer; (b) contacting the reactive species with at least one
monomer species, thereby forming a polymer coating on the surface
of the medical device; and (c) providing at least one therapeutic
agent within the polymer coating.
The therapeutic agent may be incorporated during formation of the
polymer coating or after formation of the polymer coating.
In certain embodiments, the reactive species is formed from a
derivatized monomer that is covalently bonded to the surface of the
medical device.
In certain other embodiments, the reactive species is formed from a
derivatized initiator compound that is covalently bonded to the
surface of the medical device.
The reactive species can comprise, for example, a free radical
species, a carbanion species, a carbocation species, a
Ziegler-Natta polymerization complex, a metallocene complex, and/or
an atom transfer radical polymerization initiator.
Where a free radical species is used, it can be provided, for
example, by a process comprising (a) covalently attaching a
free-radical initiator molecule to the surface or (b) covalently
attaching a species that acquires a free-radical upon exposure to a
free radical initiator molecule.
Where a carbanion species is used, it can be provided, for example,
by a process comprising (a) covalently attaching an anionic
initiator molecule to the surface or (b) covalently attaching a
species that acquires a carbanion upon exposure to an anionic
initiator molecule.
Where a carbocation species used, it can be provided, for example,
by a process comprising covalently attaching a species that
develops a carbocation upon exposure to a cationic initiator
molecule.
Where atom transfer radical polymerization is used the at least one
reactive species can be provided, for example, by a process
comprising: (a) covalently attaching an atom transfer radical
polymerization initiator molecule to the surface or (b) covalently
attaching a species that acquires a free-radical upon exposure to
an atom transfer radical polymerization initiator and an atom
transfer radical polymerization catalyst.
According to another aspect of the present invention, a medical
device with a therapeutic agent-releasing coating is provided by a
process comprising: (a) immobilizing least one polymerization
catalyst at a medical device surface, which polymerization catalyst
leads to polymerization in the presence of monomer; (b) contacting
the medical device surface with at least one monomer species,
thereby forming a polymer coating at the surface of the medical
device; and (c) providing at least one therapeutic agent within the
polymer coating.
One advantage of the present invention is that a process is
provided that allows for controlled manufacture of drug delivery
polymer coatings on medical device surfaces.
Another advantage of the present invention is that a process is
provided, which allows many medical devices to be coated at the
same time, improving manufacturing efficiency and cost
effectiveness.
The above and other embodiments and advantages of the present
invention will be readily understood by those of ordinary skill in
the art upon review of the Detailed Description and Claims to
follow.
DETAILED DESCRIPTION OF THE INVENTION
Methods for providing medical devices having
therapeutic-agent-releasing polymer coatings are provided below in
accordance with various embodiments of the invention.
Preferred medical devices for use in conjunction with the present
invention are implantable or insertable medical devices, including
catheters (for example, urinary catheters or vascular catheters),
guide wires, balloons, filters (e.g., vena cava filters), stents
(including coronary vascular stents, cerebral, urethral, ureteral,
biliary, tracheal, gastrointestinal and esophageal stents), stent
grafts, cerebral aneurysm filler coils (including GDC--Guglilmi
detachable coils--and metal coils), vascular grafts, myocardial
plugs, patches, pacemakers and pacemaker leads, heart valves,
biopsy devices or any polymer coated substrate (which can be, for
example, metallic, polymeric or ceramic) for use in the human body,
either for procedural use or as an implant.
The medical devices contemplated for use in connection with the
present invention include drug delivery medical devices that are
used for either systemic treatment or for the treatment of any
mammalian tissue or organ. Non-limiting examples of tissues and
organs include the heart, coronary or peripheral vascular system,
lungs, trachea, esophagus, brain, liver, kidney, bladder, urethra
and ureters, eye, intestines, stomach, pancreas, ovary, and
prostate; skeletal muscle; smooth muscle; breast; cartilage; and
bone.
Medical devices made in accordance with the present invention can
be placed in a wide variety of bodily locations for contact with
bodily tissue and/or fluid. Some preferred placement locations
include the coronary vasculature or peripheral vascular system
(referred to collectively herein as "the vasculature"),
gastrointestinal tract, esophagus, trachea, colon, biliary tract,
urinary tract, prostate and brain.
In some embodiments of the present invention, a polymer coating is
provided by first attaching one or more reactive species to at
least a portion of the surface of a medical device. Subsequent
contact with a monomer-containing liquid leads to chain-growth
polymerization at the site of the attached species. In this manner,
a polymer coating is produced that is attached to the surface of
the medical device.
A "monomer" is a polymerizable molecule. For example, monomers may
be small molecules, such as those listed below; or they may be
larger molecules containing polymerizable groups, for example,
polymers containing >C.dbd.C< groups. A "polymer" is composed
of two or more monomers, and includes dimers, trimers, tetramers,
etc.
Preferred monomers for embodiments of the invention that utilize
chain-growth polymerization (e.g., addition polymerization) are
unsaturated monomers, including, for example: (a) alkylene monomers
and derivatives, such as ethylene, propylene, butylenes (e.g.,
isobutylene), and fluorinated alkylene monomers (e.g.,
tetrafluoroethylene); (b) vinyl monomers and derivatives, such as
styrene, vinyl chloride, vinyl pyrrolidone, acrylonitrile, vinyl
alcohol, and vinyl acetate; and (d) acrylic acid monomers and
derivatives, such as methyl acrylate, methyl methacrylate, acrylic
acid, methacrylic acid, acrylamide, hydroxyethyl acrylate,
hydroxyethyl methacrylate, glyceryl acrylate, glyceryl
methacrylate, methacrylamide and ethacrylamide.
Polymerization can proceed via essentially any known chain-growth
polymerization mechanism, including free-radical polymerization,
cationic polymerization, anionic polymerization, Ziegler-Natta
polymerization, metallocene polymerization, and atom transfer
radical polymerization.
In some chain-growth polymerization reactions, including several of
the reactions discussed below, an initiator molecule becomes
incorporated into the polymer that is formed. In some cases, the
initiator molecule is attached to the medical device surface. A
polymer is then formed by exposing the attached initiator to
monomer, along with any desired auxiliary species (e.g.,
co-initiators, catalysts, co-catalysts, electron donors,
accelerators, sensitizers, etc.) under any desired reaction
conditions (for example, irradiation and/or heat). Examples of
initiators include free radical initiators, anionic initiators,
cationic co-initiators and atom transfer radical polymerization
initiators. For example, the medical device can be formed from a
material that provides chemically reactive groups or the surface of
the medical device can be treated with a reagent that places
chemically reactive groups on the device surface or with a coating
that supplies such groups. These groups are then reacted with
groups that are either inherently found on the initiator molecule
or are supplied to the initiator molecule (i.e., a derivatized form
of the initiator is used). Covalent attachment may be carried out
using numerous known reaction chemistries.
In other embodiments of the invention, a transformable molecule is
attached to the medical device surface, which is transformed into a
reactive species upon interaction with an initiator or catalyst
molecule. The chain growth occurs at the site of the reactive
species upon exposure to an appropriate monomer under the
appropriate conditions.
The transformable molecule is typically an unsaturated molecule,
and more typically a monomer that is derivatized for attachment to
the device surface.
To avoid the initiation of polymer chains not attached to the
surface, it is preferred, for example, to either (a) limit the
quantity of initiator or catalyst added or (b) remove excess
initiator or catalyst before the introduction of monomer.
As with the initiator molecule, attachment of the transformable
molecule can be covalent. For example, in the case where the
transformable molecule is a monomer, attachment typically occurs
through groups that are either inherently found on the monomer or
are supplied to the monomer (e.g., a derivatized form of the
monomer is used).
Specific examples include the following: (a) interaction between an
attached unsaturated molecule and a free-radical initiator can be
used to generate an attached free radical species, which leads to
chain growth in the presence of monomer, (b) interaction between an
attached unsaturated molecule and a cationic initiator can be used
to generate an attached carbocationic species, which leads to chain
growth in the presence of monomer, (c) interaction between an
attached unsaturated molecule and an anionic initiator can be used
to generate an attached carbanion species, which leads to chain
growth in the presence of monomer, (d) interaction between an
attached unsaturated molecule and a Ziegler-Natta
catalyst/co-catalyst system can be used to generate an attached
reactive species, which leads to chain growth in the presence of
monomer, (e) interaction between an attached unsaturated molecule
and a metallocene catalyst can be used to generate an attached
reactive species, which leads to chain growth in the presence of
monomer, and (f) interaction between an attached unsaturated
molecule and an atom transfer radical polymerization initiator
system can be used to generate an attached reactive species, which
leads to chain growth in the presence of monomer.
Suitable free radical initiator compounds for use in connection
with free-radical polymerization embodiments of the present
invention include hydroperoxide, peroxide, di-tert-butyl peroxide,
di-benzoyl peroxide, and azo compounds, such as
azobis(isobutyronitrile), tertiary butyl perbenzoate, di-cumyl
peroxide and potassium persulfate.
According to a specific exemplary embodiment of the invention, a
substrate surface is provided, which contains free hydroxyl groups.
Subsequently a molecule including a vinyl group is covalently
bonded to the surface. For example, vinyltrimethoxysilane can be
reacted with the --OH groups on the surface, leaving a vinyl group
attached to the surface for subsequent polymerization (e.g.,
free-radical polymerization) with a number of monomeric
species.
According to another a specific exemplary embodiment of the
invention, a free radical polymerization of methyl methacrylate is
conducted to provide a polymeric coating on the surface of a
medical device. Initially, a methyl methacrylate derivative is
covalently attached to the medical device surface
##STR00001## as shown, where R is an organic radical, typically a
hydrocarbon chain. A free radical initiator such as a peroxide
compound is added, generating a free radical species within the
attached molecule. Subsequently, methyl methacrylate monomer is
added to commence chain growth polymerization, which proceeds from
the attached molecule. The result is a medical device with a
covalently attached polymethylmethacrylate coating. Where R is an
initiator molecule attached to the surface, polymerization would
occur through the illustrated double bond.
In related embodiments, the attachment of the methacrylate
derivative can occur through the ester group. For example, a
functionalized methacrylate, such as glycidyl methacrylate, hydroxy
ethyl methacrylate, methacrylic acid, can initially be attached to
the surface. The initiator then generates the free-radicals, and
methyl methacrylate monomer is added to start polymer
formation.
Metallocene catalysts are coordination compounds that are
cyclopentadienyl derivatives of metal-containing ions (e.g.,
transition metal ions or transition metal halide ions). Examples of
metallocene catalysts for use in metallocene polymerization
embodiments of the present invention include ferrocene and
bis-chlorozirconocene. Their use in the polymerization of
unsaturated monomers is well known.
Ziegler-Natta catalysts are also well known. Typical Ziegler-Natta
catalysts for use in Ziegler-Natta polymerization embodiments of
the present invention include a transition metal compound, for
example, titanium halides such as TiCl.sub.3 or TiCl.sub.4, in
combination with an organo aluminum compound, for example, a
trialkyl aluminum or dialkylaluminum halide such as
Al(CH.sub.2H.sub.5).sub.2Cl or Al(C.sub.2H.sub.5).sub.3. An
electron donor is also typically included.
In an atom transfer radical polymerization process, one or more
radically polymerizable monomers are polymerized in the presence of
an initiator and a catalyst, which includes a transition metal
complexed by one or more ligands. The transition metal is any
transition metal compound that can participate in a redox cycle
with the initiator and the growing polymer chain. Transition metal
catalysts include those represented by the following general
formula TM.sup.n+X.sub.n, where TM is the transition metal, n is
the formal charge on the transition metal having a value of from 0
to 7, and X is a counterion or covalently bonded component.
Examples of the transition metal (TM) include, but are not limited
to, Cu, Fe, Au, Ag, Hg, Pd, Pt, Co, Mn, Ru, Mo, Nb and Zn. Examples
of X include, but are not limited to, halide, hydroxy, oxygen,
C.sub.1-C.sub.6 alkoxy, cyano, cyanato, thiocyanato and azido. A
preferred transition metal is Cu(I) and X is preferably halide.
Ligands include compounds having one or more nitrogen, oxygen,
phosphorus and/or sulfur atoms, which can coordinate to the
transition metal catalyst compound, such as unsubstituted and
substituted pyridines and bipyridines; porphyrins; cryptands; crown
ethers; polyamines; alkylene glycols; carbon monoxide; as well as
coordinating monomers, for example, styrene, acrylonitrile and
hydroxyalkyl (meth)acrylates. Initiators that may be used include
organic compounds, such as aliphatic compounds, cycloaliphatic
compounds, aromatic compounds, polycyclic aromatic compounds,
heterocyclic compounds, sulfonyl compounds, sulfenyl compounds,
esters of carboxylic acids, nitriles, ketones, phosphonates and
combinations thereof, having one or more radically transferable
groups such as, for example, cyano, cyanato, thiocyanato, azido,
halide groups and combinations thereof. Preferably, the radically
transferable groups of the monomeric initiator are selected from
halide groups (e.g., chloride, bromide and iodide). Additional
information can be found, for example, in U.S. Pat. Nos. 5,807,937
and 6,326,420, which are hereby incorporated by reference.
According to a specific embodiment of the invention, an atom
transfer radical polymerization process is conducted to provide a
polymeric coating on the surface of a medical device. Initially, an
alky halide initiator molecule is attached to the medical device
surface, to yield, for example,
##STR00002## where R is an organic radical, such as a hydrocarbon
chain. A transition metal catalyst, such as Cu(I)Cl, and a monomer,
such as styrene (as noted above, coordinating monomers such as
styrene can be used as a ligand), are introduced to commence chain
growth polymerization, which proceeds from the initiator molecule.
The result is a medical device with a covalently attached
polystyrene coating.
Suitable anionic initiators for use in anionic polymerization
embodiments of the present invention include alkyl metal compounds,
such as methyl lithium, ethyl lithium, methyl sodium, isopropyl
lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium,
n-dodecyllithium, cyclohexyllithium, 4-cyclohexyllithium butyl
sodium, lithium naphthalene, sodium naphthalene, potassium
naphthalene, cesium naphthalene, phenyl sodium, phenyl lithium,
benzyl lithium, cumyl sodium, cumyl potassium, methyl potassium,
ethyl potassium, and so forth.
Cationic initiators for use in cationic polymerization embodiments
the present invention are generally of the Lewis acid type, for
example, aluminum trichloride, boron trifluoride, boron trifluoride
etherate complexes, titanium tetrachloride and the like. If
desired, a cationic co-initiator can be added. Suitable cationic
co-initiators include tertiary alkyl halides (e.g.,
t-butylchloride), tert-ester, tert-ether, tert-hydroxyl and
tert-halogen containing compounds, such as cumyl esters of
hydrocarbon acids, alkyl cumyl ethers, cumyl halides and cumyl
hydroxyl compounds and hindered versions of the same. Also,
electron pair donors such as dimethyl acetamide, dimethyl
sulfoxide, or dimethyl phthalate can be added, as can
proton-scavengers that scavenge water, such as
2,6-di-tert-butylpyridine, 4-methyl-2,6-di-tert-butylpyridine,
1,8-bis(dimethylamino)-naphthalene, or diisopropylethyl amine.
In one preferred embodiment, the reaction is commenced by removing
a tert-ester, tert-ether, tert-hydroxyl or tert-halogen group from
a co-initiator molecule that has been covalently attached to the
surface of a medical device by reacting it with the Lewis acid
initiator in a suitable solvent system (e.g., a mixture of polar
and non-polar solvents such as methyl chloride and hexanes) in the
presence of an electron pair donor. In place of the tert-leaving
groups is a quasi-stable or "living" cation, which is stabilized by
the surrounding tertiary carbons as well as the polar solvent
system and electron pair donors. Monomer, such as isobutylene, is
introduced, which cationically propagates or polymerizes from each
cation on the attached co-initiator molecule. Because the initiator
complex is unstable, the monomer (e.g., isobutylene) is commonly
added to the reaction before the addition of the Lewis acid
initiator (e.g., TiCl.sub.4). If desired, an additional monomer
such as styrene can subsequently added to form a block copolymer.
In this connection, it is noted that a mono-functional initiator
produces a diblock copolymer (e.g., polyisobutylene-polystyrene)
and a di-functional initiator attached to the surface is used to
create a triblock copolymer (e.g.,
polystyrene-polyisobutylene-polystyrene). The reaction can be
terminated by adding a termination molecule such as methanol, water
and the like. Further information can be found, for example, in
U.S. Pat. Nos. 5,741,331 and 4,946,899, which are hereby
incorporated by reference.
In the embodiments discussed above, a polymer coating is provided
by attaching one or more species to the surface of a medical
device, followed by contact with a monomer, leading to chain-growth
polymerization at the site of the attached species. In other
embodiments, however, the surface is provided either completely or
in part with a catalyst that is used to cause the polymerization
reaction at the surface. Subsequently, the medical device exposed
to monomer, which then polymerizes in the vicinity of the
immobilized catalyst. The catalyst can be immobilized, for example,
by covalently bonding it to the surface (including, for example, a
coating surface), by physically embedding it in the surface, by
plating it onto the surface, by adsorbing it onto the surface, by
absorbing it into the surface, and so forth. As the reaction
progresses, polymer merges into polymer and thus the integrity of
the coating is created by the continuity of the polymer.
For example, the catalyst can be covalently bonded by, for example,
treating the surface of the medical device with a reagent that
places chemically reactive groups on the device surface or with a
coating that supplies such groups. These groups are then reacted
with groups that are either inherently found on the catalyst or are
supplied to the catalyst (i.e., a derivatized form of the catalyst
is used). Covalent attachment of the catalyst may be carried out
using numerous known reaction chemistries.
As another example, the surface of the medical device such as a
stent can be at least partially covered by a metallic catalyst, for
instance, by plating the medical device with a platinum group
catalyst. The platinum group metal is subsequently used to catalyze
a polymerization reaction, for example, the polymerization of
silicone.
The polymerization rates in this embodiment are preferably much
greater than the rate at which the formed polymer diffuses away
from the surface. Therefore, a polymer is formed that is not
covalently attached to the surface of the device, but is
concentrated at that surface.
In some embodiments, crosslinking is used to change the properties
of the resulting polymer coating. Crosslinking can also provide
stronger interaction with the medical device surface, for example,
by improving the ability of the polymer to form a unitary mass that
surrounds the medical device. Crosslinking strategies are known in
the art and include providing the monomer with functional groups
that are crosslinkable, e.g., using a crosslinking agent or via
photoreaction.
Where chain-growth polymerization reactions are employed,
immobilized catalysts include metallocene catalysts, Ziegler-Natta
catalysts, atom transfer radical and polymerization catalysts.
Where a multi-component catalyst is used, one component of the
system may be immobilized. Numerous preferred chain-growth polymers
are listed above.
Where step-growth polymerization reactions (typically condensation
polymerization reactions) are employed, preferred monomers include
terephthalic acid, butanediol, ethylene glycol, toluene
diisocyanate (TDI), diphenylmethane diisocyanate (MDI), polyether
polyols, hexamethylene diamine, adipic acid, bis-phenol A, diphenyl
carbonate (see, e.g., U.S. Pat. No. 6,323,304, which is hereby
incorporated by reference), while preferred catalysts for
immobilization include the previously discussed platinum group
metals, as well as dibutyl tin dilaurate and stannous octoate.
In some step-growth embodiments, dendrimers can be used, allowing
branched polymers to be formed.
In all of the above embodiments, polymerization proceeds upon
contact with a liquid that contains the selected monomer, as well
any other desired components, such as initiators, co-initiators,
catalysts, co-catalysts, electron donors and so forth. However, the
liquid preferably does not contain sufficient components to cause
initiation not attached to the surface. Instead, polymerization
preferably occurs at or near the surface upon interaction with
species that are provided at the device surface (e.g., initiator,
catalyst, etc.).
The monomer containing liquid also typically includes an
appropriate solvent system. However, in certain embodiments,
polymerization can also be conducted in the absence of solvent
(i.e., via a "neat" or "bulk" polymerization process).
The monomer containing liquid can be applied to the medical device
(for example, by spraying or rinsing the medical device with the
liquid) or, more preferably, the medical device can be immersed in
the monomer containing liquid. In these embodiments, multiple
medical devices can be produced concurrently.
The thickness of the coating that is formed on the medical device
can be controlled in a number of ways, including limiting the
amount of monomer that is present, terminating the reaction after a
sufficient coating thickness is a achieved, or separating the
medical device from the monomer containing liquid after a
sufficient coating is a achieved.
Using the above techniques, a wide variety of polymeric coatings
can be created. Polymers include (a) polyalkylenes and derivatives
such as polyethylenes, polypropylenes, poly-4-methyl-pen-1-eness,
polybutylenes (including polybut-1-enes and polyisobutylenes), and
fluorinated polyalkylenes (including polytetrafluoroethylenes); (b)
polyvinyl polymers and derivatives, such as polystyrenes, polyvinyl
chlorides, polyvinyl pyrrolidones, polyacrylonitriles, polyvinyl
alcohols, polyvinyl ethers, polyvinyl pyridines, and polyvinyl
acetates; and (d) acrylic acid polymers and derivatives, such as
methylacrylate polymers, methyl methacrylate polymers, acrylic acid
polymers, methacrylic acid polymers, acrylamide polymers,
hydroxyethyl acrylate polymers, hydroxyethyl methacrylate polymers,
glyceryl acrylate polymers, glyceryl methacrylate polymers,
methacrylamide polymers and ethacrylamide polymers, (e) step-growth
polymers such as poly(esters), nylons, poly(urethanes),
poly(carbonates), and (f) ring-opening polymerization products,
such as poly(.epsilon.-caprolactone) (e.g., nylon 6),
poly(L-lactide), poly(glycolide) and poly(p-dioxanone). Also
included are copolymers (e.g., block and random copolymers) of the
above, including styrene-butadiene copolymers,
acrylonitrile-styrene copolymers, acrylonitrile-butadiene-styrene
copolymers, styrene-isobutylene copolymers, ethylene-alpha-olefin
copolymers, ethylene-methacrylic acid copolymers, ethylene-acrylic
acid copolymers, ethylene-methyl methacrylate copolymers and
ethylene-vinyl acetate copolymers, ethylene-tetrafluoroethylene
copolymers, anhydride functionalized copolymers, such as
styrene-maleic anhydride, methylvinylether-maleic anhydride, ring
opening copolymers such as copolymers of poly(glycolides),
poly(lactides), poly(caprolactones) and poly(p-dioxanone),
copolymers of polyamides and ethers, and copolymers of esters and
ethers. Random copolymers can be made, for example, by exposing the
medical device to a mixture of monomers, while block copolymers can
be made, for example, by sequential exposure to different
monomers.
The polymer coatings of the present invention are preferably
biocompatible for their intended purpose. This means, for example,
that the coatings typically do not lead to severe, long-lived or
escalating adverse biological responses (which are distinguished,
for instance, from the mild, transient inflammation that
accompanies implantation of essentially all foreign objects into a
living organism).
After the polymer coating is formed, the medical device may be
washed in an appropriate solvent to remove unreacted monomer (as
well as any other residual species, including initiators,
co-initiators, catalysts, co-catalysts and so forth).
A therapeutic agent is preferably provided within the polymer
coating on the medical device surface. In some instances, the
therapeutic agent can be provided within the polymer coating
concurrently with polymer formation (for example, by including the
therapeutic agent in the monomer containing liquid). In other
instances, the therapeutic agent is incorporated after polymer
formation. For example, the therapeutic agent can be dissolved or
dispersed within a liquid medium, and the liquid medium contacted
with the polymer coating, for example by applying the liquid to the
polymer coating (e.g., by spraying or rinsing) or by immersing at
least a portion of the medical device within the liquid.
Where the polymer is covalently attached to the medical device
surface, the polymer can be contacted with a solvent that would
otherwise dissolve the attached polymer. In this way, the polymer
can be solubilized, without being removed from the device surface.
For example, such a solvent can be used to remove unreacted monomer
and/or other residual species from the polymer coating, with
diffusion of species out of the polymer being enhanced by the fact
that the polymer is solubilized. Alternatively, a solvent of this
type can be used to dissolve/disperse a therapeutic agent, which is
then contacted with the coating. Analogous to species removal,
diffusion of species (in this case, therapeutic agent) into the
polymer coating is increased by solubilizing the polymer. Once the
solvent is removed, the therapeutic agent is trapped within the
polymer.
Therapeutic agents useful in connection with the present invention
include essentially any therapeutic agent that is compatible with
the selected polymeric coating (e.g., is not adversely affected by
the polymeric coating and can be released from the polymeric
coating). Therapeutic agents may be used singly or in
combination.
"Therapeutic agents", "pharmaceutically active agents",
"pharmaceutically active materials", "drugs" and other related
terms may be used interchangeably herein and include genetic
therapeutic agents, non-genetic therapeutic agents and cells.
Exemplary non-genetic therapeutic agents include: (a)
anti-thrombotic agents such as heparin, heparin derivatives,
urokinase, and PPack (dextrophenylalanine proline arginine
chloromethylketone); (b) anti-inflammatory agents such as
dexamethasone, prednisolone, corticosterone, budesonide, estrogen,
sulfasalazine and mesalamine; (c)
antineoplastic/antiproliferative/anti-mitotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, angiopeptin, monoclonal
antibodies capable of blocking smooth muscle cell proliferation,
and thymidine kinase inhibitors; (d) anesthetic agents such as
lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as
D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing
compound, heparin, hirudin, antithrombin compounds, platelet
receptor antagonists, anti-thrombin antibodies, anti-platelet
receptor antibodies, aspirin, prostaglandin inhibitors, platelet
inhibitors and tick antiplatelet peptides; (f) vascular cell growth
promoters such as growth factors, transcriptional activators, and
translational promoters; (g) vascular cell growth inhibitors such
as growth factor inhibitors, growth factor receptor antagonists,
transcriptional repressors, translational repressors, replication
inhibitors, inhibitory antibodies, antibodies directed against
growth factors, bifunctional molecules consisting of a growth
factor and a cytotoxin, bifunctional molecules consisting of an
antibody and a cytotoxin; (h) protein kinase and tyrosine kinase
inhibitors (e.g., tyrphostins, genistein, quinoxalines); (i)
prostacyclin analogs; (j) cholesterol-lowering agents; (k)
angiopoietins; (l) antimicrobial agents such as triclosan,
cephalosporins, aminoglycosides and nitrofurantoin; (m) cytotoxic
agents, cytostatic agents and cell proliferation affectors; (n)
vasodilating agents; and (o) agents that interfere with endogenous
vasoactive mechanisms.
Exemplary genetic therapeutic agents include anti-sense DNA and RNA
as well as DNA coding for: (a) anti-sense RNA, (b) tRNA or rRNA to
replace defective or deficient endogenous molecules, (c) angiogenic
factors including growth factors such as acidic and basic
fibroblast growth factors, vascular endothelial growth factor,
epidermal growth factor, transforming growth factor .alpha. and
.beta., platelet-derived endothelial growth factor,
platelet-derived growth factor, tumor necrosis factor .alpha.,
hepatocyte growth factor and insulin-like growth factor, (d) cell
cycle inhibitors including CD inhibitors, and (e) thymidine kinase
("TK") and other agents useful for interfering with cell
proliferation. Also of interest is DNA encoding for the family of
bone morphogenic proteins ("BMP's"), including BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11,
BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred
BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These
dimeric proteins can be provided as homodimers, heterodimers, or
combinations thereof, alone or together with other molecules.
Alternatively, or in addition, molecules capable of inducing an
upstream or downstream effect of a BMP can be provided. Such
molecules include any of the "hedgehog" proteins, or the DNA's
encoding them.
Vectors of interest for delivery of genetic therapeutic agents
include (a) plasmids, (b) viral vectors such as adenovirus,
adenoassociated virus and lentivirus, and (c) non-viral vectors
such as lipids, liposomes and cationic lipids.
Cells include cells of human origin (autologous or allogeneic),
including stem cells, or from an animal source (xenogeneic), which
can be genetically engineered if desired to deliver proteins of
interest.
A number of the above therapeutic agents and several others have
also been identified as candidates for vascular treatment regimens,
for example, as agents targeting restenosis. Such agents are
appropriate for the practice of the present invention and include
one or more of the following: (a) Ca-channel blockers including
benzothiazapines such as diltiazem and clentiazem, dihydropyridines
such as nifedipine, amlodipine and nicardapine, and
phenylalkylamines such as verapamil, (b) serotonin pathway
modulators including: 5-HT antagonists such as ketanserin and
naftidrofuryl, as well as 5-HT uptake inhibitors such as
fluoxetine, (c) cyclic nucleotide pathway agents including
phosphodiesterase inhibitors such as cilostazole and dipyridamole,
adenylate/guanylate cyclase stimulants such as forskolin, as well
as adenosine analogs, (d) catecholamine modulators including
.alpha.-antagonists such as prazosin and bunazosine,
.beta.-antagonists such as propranolol and
.alpha./.beta.-antagonists such as labetalol and carvedilol, (e)
endothelin receptor antagonists, (f) nitric oxide donors/releasing
molecules including organic nitrates/nitrites such as
nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic
nitroso compounds such as sodium nitroprusside, sydnonimines such
as molsidomine and linsidomine, nonoates such as diazenium diolates
and NO adducts of alkanediamines, S-nitroso compounds including low
molecular weight compounds (e.g., S-nitroso derivatives of
captopril, glutathione and N-acetyl penicillamine) and high
molecular weight compounds (e.g., S-nitroso derivatives of
proteins, peptides, oligosaccharides, polysaccharides, synthetic
polymers/oligomers and natural polymers/oligomers), as well as
C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds and
L-arginine, (g) ACE inhibitors such as cilazapril, fosinopril and
enalapril, (h) ATII-receptor antagonists such as saralasin and
losartin, (i) platelet adhesion inhibitors such as albumin and
polyethylene oxide, (j) platelet aggregation inhibitors including
aspirin and thienopyridine (ticlopidine, clopidogrel) and GP
IIb/IIIa inhibitors such as abciximab, epitifibatide and tirofiban,
(k) coagulation pathway modulators including heparinoids such as
heparin, low molecular weight heparin, dextran sulfate and
.beta.-cyclodextrin tetradecasulfate, thrombin inhibitors such as
hirudin, hirulog, PPACK (D-phe-L-propyl-L-arg-chloromethylketone)
and argatroban, FXa inhibitors such as antistatin and TAP (tick
anticoagulant peptide), Vitamin K inhibitors such as warfarin, as
well as activated protein C, (l) cyclooxygenase pathway inhibitors
such as aspirin, ibuprofen, flurbiprofen, indomethacin and
sulfinpyrazone, (m) natural and synthetic corticosteroids such as
dexamethasone, prednisolone, methprednisolone and hydrocortisone,
(n) lipoxygenase pathway inhibitors such as nordihydroguairetic
acid and caffeic acid, (o) leukotriene receptor antagonists, (p)
antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 and
ICAM-1 interactions, (r) prostaglandins and analogs thereof
including prostaglandins such as PGE1 and PGI2 and prostacyclin
analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and
beraprost, (s) macrophage activation preventers including
bisphosphonates, (t) HMG-CoA reductase inhibitors such as
lovastatin, pravastatin, fluvastatin, simvastatin and cerivastatin,
(u) fish oils and omega-3-fatty acids, (v) free-radical
scavengers/antioxidants such as probucol, vitamins C and E,
ebselen, trans-retinoic acid and SOD mimics, (w) agents affecting
various growth factors including FGF pathway agents such as bFGF
antibodies and chimeric fusion proteins, PDGF receptor antagonists
such as trapidil, IGF pathway agents including somatostatin analogs
such as angiopeptin and ocreotide, TGF-.beta. pathway agents such
as polyanionic agents (heparin, fucoidin), decorin, and TGF-.beta.
antibodies, EGF pathway agents such as EGF antibodies, receptor
antagonists and chimeric fusion proteins, TNF-.alpha. pathway
agents such as thalidomide and analogs thereof, Thromboxane A2
(TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben
and ridogrel, as well as protein tyrosine kinase inhibitors such as
tyrphostin, genistein and quinoxaline derivatives, (x) MMP pathway
inhibitors such as marimastat, ilomastat and metastat, (y) cell
motility inhibitors such as cytochalasin B, (z)
antiproliferative/antineoplastic agents including antimetabolites
such as purine analogs (6-mercaptopurine), pyrimidine analogs
(e.g., cytarabine and 5-fluorouracil) and methotrexate, nitrogen
mustards, alkyl sulfonates, ethylenimines, antibiotics (e.g.,
daunorubicin, doxorubicin), nitrosoureas, cisplatin, agents
affecting microtubule dynamics (e.g., vinblastine, vincristine,
colchicine, paclitaxel and epothilone), caspase activators,
proteasome inhibitors, angiogenesis inhibitors (e.g., endostatin,
angiostatin and squalamine), rapamycin, cerivastatin, flavopiridol
and suramin, (aa) matrix deposition/organization pathway inhibitors
such as halofuginone or other quinazolinone derivatives and
tranilast, (bb) endothelialization facilitators such as VEGF and
RGD peptide, and (cc) blood rheology modulators such as
pentoxifylline.
Several of the above and numerous additional therapeutic agents
appropriate for the practice of the present invention are also
disclosed in U.S. Pat. No. 5,733,925 assigned to NeoRx Corporation,
the entire disclosure of which is incorporated by reference.
A wide range of therapeutic agent loadings can be used in
connection with the above polymeric coatings, with the amount of
loading being readily determined by those of ordinary skill in the
art and ultimately depending upon the condition to be treated, the
nature of the therapeutic agent itself, the avenue by which the
therapeutic-agent-loaded polymeric coating is administered to the
intended subject, and so forth. The loaded polymeric coating will
frequently comprise from 1% or less to 70 wt % or more therapeutic
agent.
Various aspects of the invention relating to the above enumerated
in the following paragraphs:
Aspect 1. A method of providing a medical device with a therapeutic
agent-releasing polymer coating comprising: (a) attaching at least
one reactive species to a medical device surface, said reactive
species leading to chain growth polymerization in the presence of
monomer; (b) contacting said reactive species with at least one
monomer species, thereby forming a polymer coating on the surface
of the medical device; and (c) providing at least one therapeutic
agent within said polymer coating.
Aspect 2. The method of Aspect 1, wherein at least one therapeutic
agent is incorporated during formation of the polymer coating.
Aspect 3. The method of Aspect 1, wherein at least one therapeutic
agent is incorporated after formation of the polymer coating.
Aspect 4. The method of Aspect 1, wherein the medical device is an
implantable or insertable medical device.
Aspect 5. The method of Aspect 4, wherein the medical device is a
stent.
Aspect 6. An implantable or insertable medical device made by the
method of Aspect 1.
Aspect 7. The method of Aspect 1, wherein said at least one monomer
species comprises an unsaturated monomer.
Aspect 8. The method of Aspect 1, wherein said polymer is selected
from polyalkylenes and derivatives, vinyl polymers and derivatives,
acrylic acid polymers and derivatives, and copolymers thereof.
Aspect 9. The method of Aspect 1, wherein said polymer is selected
from ethylene vinyl acetate and styrene-isobutylene copolymers.
Aspect 10. The method of Aspect 1, wherein said at least one
reactive species comprises a free radical species.
Aspect 11. The method of Aspect 10, wherein the free radical
species is provided by a process comprising (a) covalently
attaching a free-radical initiator molecule to the surface or (b)
covalently attaching a species that acquires a free-radical upon
exposure to a free radical initiator molecule.
Aspect 12. The method of Aspect 1, wherein said at least one
reactive species comprises a carbanion species.
Aspect 13. The method of Aspect 12, wherein the carbanion species
is provided by a process comprising (a) covalently attaching an
anionic initiator molecule to the surface or (b) covalently
attaching a species that acquires a carbanion upon exposure to an
anionic initiator molecule.
Aspect 14. The method of Aspect 1, wherein said at least one
reactive species comprises a carbocation species.
Aspect 15. The method of Aspect 14, wherein the carbocation species
is provided by a process comprising covalently attaching a species
that develops a carbocation upon exposure to a cationic initiator
molecule.
Aspect 16. The method of Aspect 1, wherein said at least one
reactive species comprise a Ziegler-Natta polymerization
complex.
Aspect 17. The method of Aspect 1, wherein said at least one
reactive species comprises a metallocene complex.
Aspect 18. The method of Aspect 1, wherein said at least one
reactive species comprises an atom transfer radical polymerization
initiator.
Aspect 19. The method of Aspect 18, wherein the at least one
reactive species is provided by a process comprising (a) covalently
attaching an atom transfer radical polymerization initiator
molecule to the surface or (b) covalently attaching a species that
acquires a free-radical upon exposure to an atom transfer radical
polymerization initiator and an atom transfer radical
polymerization catalyst.
Aspect 20. The method of Aspect 1, wherein the at least one
reactive species is formed from a derivatized monomer that is
covalently bonded to the surface of the medical device.
Aspect 21. The method of Aspect 1, wherein the at least one
reactive species is formed from a derivatized initiator compound
that is covalently bonded to the surface of the medical device.
Aspect 22. A method of providing a medical device with a
therapeutic agent-releasing coating comprising: (d) immobilizing
least one polymerization catalyst at a medical device surface, said
polymerization catalyst leading to polymerization in the presence
of monomer; (e) contacting the medical device surface with at least
one monomer species, thereby forming a polymer coating at the
medical device surface; and (f) providing at least one therapeutic
agent within said polymer coating.
Aspect 23. The method of Aspect 22, wherein the at least one
polymerization catalyst is immobilized by covalently bonding it to
said surface.
Aspect 24. The method of Aspect 22, wherein the at least one
polymerization catalyst is immobilized by physically embedding it
in said surface.
Aspect 25. The method of Aspect 22, wherein the medical device
surface is at least partially covered by a metal catalyst.
Aspect 26. The method of Aspect 22, further comprising
cross-linking said polymer coating.
Aspect 27. The method of Aspect 22, wherein the at least one
monomer species comprises a dendrimer.
Aspect 28. The method of Aspect 22, wherein at least one
therapeutic agent is provided within the polymer coating during
formation of the polymer coating.
Aspect 29. The method of Aspect 22, wherein at least one
therapeutic agent is provided within the polymer coating after
formation of the polymer coating.
Aspect 30. The method of Aspect 22, wherein the medical device is
an implantable or insertable medical device.
Aspect 31. The method of Aspect 30, wherein the medical device is a
stent.
Aspect 32. An implantable or insertable medical device made by the
method of Aspect 22.
Aspect 33. The method of Aspect 22, wherein said polymer is
selected from ethylene vinyl acetate copolymers,
poly(.epsilon.-caprolactone), styrene-isobutylene copolymers and
silicone.
Although various embodiments are specifically illustrated and
described herein, it will be appreciated that modifications and
variations of the present invention are covered by the above
teachings and are within the purview of the appended claims without
departing from the spirit and intended scope of the invention.
* * * * *